Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.

中文翻译：

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复发性和难治性多发性骨髓瘤的治疗：新药、抗体、免疫疗法等。

尽管取得了巨大进步，多发性骨髓瘤 (MM) 的治疗仍然具有挑战性。多种因素会影响 MM 复发/进展时的治疗决定或使用哪种治疗方案。最近的主要随机对照试验 (RCT) 显示无进展生存期 (PFS) 差异很大，中位时间为 4 个月 (MM-003) 到 23.6 个月 (ASPIRE)。基于这些随机对照试验，下一代蛋白酶体抑制剂（卡非佐米和伊沙佐米）、下一代免疫调节剂（泊马度胺）和单克隆抗体（elotuzumab 和 daratumumab）被批准用于治疗复发和难治性多发性骨髓瘤。达雷木单抗以 CD38 为靶点，具有多种作用机制，包括调节免疫抑制性骨髓微环境。除了在难治性多发性骨髓瘤中具有显着的单药活性外，达雷妥尤单抗与来那度胺/地塞米松或硼替佐米/地塞米松联合使用时，在多发性骨髓瘤中产生了深度缓解和优异的无进展生存期 (PFS)。其他抗 CD38 抗体，例如 isatuximab 和 MOR202，正在接受评估。靶向 SLAMF7 的 Elotuzumab 与来那度胺/地塞米松联合使用时产生了优异的缓解率和 PFS。这些下一代新型药物和/或抗体的新组合正在进行临床试验。Venetoclax 是一种抑制 BCL2 的口服 BH3 模拟物，在 t(11;14) 的 MM 中显示出单药活性，并且正在与硼替佐米/地塞米松联合进行研究。Selinexor 是一种 Exportin-1 抑制剂，在四难治性或五难治性 MM（包括对 daratumumab 耐药的患者）中取得了有希望的结果。Pembrolizumab 是一种抗 PD1 检查点抑制剂，正在与来那度胺/地塞米松或泊马度胺/地塞米松联合进行测试。靶向 B 细胞成熟抗原的嵌合抗原受体 T 细胞在 RRMM 中产生了深度反应。最后，挽救性自体干细胞移植 (ASCT) 仍然是首次 ASCT 后 MM 复发/进展的重要治疗方法。本文总结了这些药物的临床试验数据，强调了对 RCT 的谨慎解释，并提出了复发/难治性 MM 的挽救治疗算法。